The chondrodysplasias are a heterogeneous group of genetic disorders presenting with disproportionate short stature and other skeletal anomalies. We propose to study two chondrodysplasias affecting primarily the limb/ ectrodactyly and Grebe syndrome. Both disorders are inherited as Mendelian traits and their etiology is unknown. Since histopathological and biochemical studies have yielded no clues regarding their cause, we plan to study these disorders with a combination of positional and functional mapping strategies. Our main objective is to map the loci of the aforementioned disorders. To this end, panels of families segregating ectrodactyly and Grebe syndrome will be genotyped. Since the clinical manifestations of Grebe syndrome and ectrodactyly suggest an error in developmental patterning, we will be using homeobox-containing and other growth factor genes as candidates for linkage analysis. Positional mapping will be used as a complimentary approach. The families will be typed for a series of index markers regularly distributed in the genome. These markers are highly polymorphic VNTRs and VNDRs generated primarily by PCR amplification. If genetic linkage is not established to any of the index markers, then an exclusion map will be generated, the main purpose of which will be to highlight the non-excluded area(s) of the genome to be targeted for saturation mapping. The second objective of this project will be the identification of mutations in the particular genes found linked to these two disorders. Genomic or cDNA from affected individuals will be subjected to single strand conformation polymorphism analysis (SSCP) to screen for mutations to be followed by DNA sequencing. The long term goal of this project is the mapping and cloning of genes regulating limb development. Accomplishment of this goal will make possible the study of mechanisms underlying the various chondrodysplasias and form the basis of designing rational therapies for the treatment of short stature and other skeletal manifestations.